| 1. |
- Adolphe, Christelle, et al.
(författare)
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SOX9 Defines Distinct Populations of Cells in SHH Medulloblastoma but Is Not Required for Math1-Driven Tumor Formation
- 2021
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Ingår i: Molecular Cancer Research. - : American Association For Cancer Research (AACR). - 1541-7786 .- 1557-3125. ; 19:11, s. 1831-1839
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is the most common malignant pediatric brain tumor and there is an urgent need for molecularly targeted and subgroup-specific therapies. The stem cell factor SOX9, has been proposed as a potential therapeutic target for the treatment of Sonic Hedgehog medulloblastoma (SHH-MB) subgroup tumors, given its role as a downstream target of Hedgehog signaling and in functionally promoting SHH-MB metastasis and treatment resistance. However, the functional requirement for SOX9 in the genesis of medulloblastoma remains to be determined. Here we report a previously undocumented level of SOX9 expression exclusively in proliferating granule cell precursors ( GCP) of the postnatal mouse cerebellum, which function as the medulloblastoma-initiating cells of SHH-MBs. Wild-type GCPs express comparatively lower levels of SOX9 than neural stem cells and mature astroglia and SOX9(low) GCP-like tumor cells constitute the bulk of both infant (Math1Cre: Ptch1(lox/lox)) and adult (Ptch1(LacZ/+)) SHH-MB mouse models. Human medulloblastoma single-cell RNA data analyses reveal three distinct SOX9 populations present in SHH-MB and noticeably absent in other medulloblastoma subgroups: SOX9(+)MATH1(+) (GCP), SOX9(+)GFAP(+) (astrocytes) and SOX9(+)MATH1(+)GFAP(+) (potential tumor-derived astrocytes). To functionally address whether SOX9 is required as a downstream effector of Hedgehog signaling in medulloblastoma tumor cells, we ablated Sox9 using a Math1Cre model system. Surprisingly, targeted ablation of Sox9 in GCPs (Math1Cre:Sox9(lox/lox)) revealed no overt phenotype and loss of Sox9 in SHH-MB (Math1Cre:Ptch1(lox/lox);Sox9(lox/lox)) does not affect tumor formation.
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| 2. |
- Brown, Joel S., et al.
(författare)
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Updating the Definition of Cancer
- 2023
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Ingår i: Molecular cancer research : MCR. - 1557-3125. ; 21:11, s. 1142-1147
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Tidskriftsartikel (refereegranskat)abstract
- Most definitions of cancer broadly conform to the current NCI definition: "Cancer is a disease in which some of the body's cells grow uncontrollably and spread to other parts of the body." These definitions tend to describe what cancer "looks like" or "does" but do not describe what cancer "is" or "has become." While reflecting past insights, current definitions have not kept pace with the understanding that the cancer cell is itself transformed and evolving. We propose a revised definition of cancer: Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection. We believe this definition captures the essence of the majority of previous and current definitions. To the simplest definition of cancer as a disease of uncontrolled proliferation of cells, our definition adds in the adjective "transformed" to capture the many tumorigenic processes that cancer cells adopt to metastasize. To the concept of uncontrolled proliferation of transformed cells, our proposed definition then adds "subject to evolution by natural selection." The subject to evolution by natural selection modernizes the definition to include the genetic and epigenetic changes that accumulate within a population of cancer cells that lead to the lethal phenotype. Cancer is a disease of uncontrolled proliferation by transformed cells subject to evolution by natural selection.
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| 3. |
- Cerezo-Magaña, Myriam, et al.
(författare)
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Hypoxic induction of exosome uptake through proteoglycan-dependent endocytosis fuels the lipid droplet phenotype in Glioma
- 2021
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Ingår i: Molecular Cancer Research. - : American Association For Cancer Research (AACR). - 1541-7786 .- 1557-3125. ; 19:3, s. 528-540
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Tidskriftsartikel (refereegranskat)abstract
- As an adaptive response to hypoxic stress, aggressive tumors rewire their metabolic phenotype into increased malignant behavior through extracellular lipid scavenging and storage in lipid droplets (LD). However, the underlying mechanisms and potential lipid source retrieved in the hypoxic tumor microenvironment remain poorly understood. Here, we show that exosome-like extracellular vesicles (EV), known as influential messengers in the tumor microenvironment, may also serve anabolic functions by transforming hypoxic, patient-derived human glioblastoma cell lines into the LDþ phenotype. EVs were internalized via a hypoxia-sensitive, endocytic mechanism that fueled LD formation through direct lipid transfer, and independently of fatty acid synthase activity. EVs can enter cells through multiple and yet ill-defined pathways. On a mechanistic level, we found that hypoxia-mediated EV uptake depends on increased heparan sulfate proteoglycan (HSPG) endocytosis that preferentially followed the lipid raft pathway. The functional relevance of HSPG was evidenced by the reversal of EV-mediated LD loading by targeting of HSPG receptor function.
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| 4. |
- Chandran, Vineesh Indira, et al.
(författare)
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Hypoxia Attenuates Trastuzumab Uptake and Trastuzumab-Emtansine (T-DM1) Cytotoxicity through Redistribution of Phosphorylated Caveolin-1
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:4, s. 644-656
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Tidskriftsartikel (refereegranskat)abstract
- The antibody-drug conjugate trastuzumab-emtansine (T-DM1) offers an additional treatment option for patients with HER2-amplified tumors. However, primary and acquired resistance is a limiting factor in a significant subset of patients. Hypoxia, a hallmark of cancer, regulates the trafficking of several receptor proteins with potential implications for tumor targeting. Here, we have investigated how hypoxic conditions may regulate T-DM1 treatment efficacy in breast cancer. The therapeutic effect of T-DM1 and its metabolites was evaluated in conjunction with biochemical, flow cytometry, and high-resolution imaging studies to elucidate the functional and mechanistic aspects of hypoxic regulation. HER2 and caveolin-1 expression was investigated in a well-annotated breast cancer cohort. Wefind that hypoxia fosters relative resistance to T-DM1 in HER2(+) cells (SKBR3 and BT474). This effect was not a result of deregulated HER2 expression or resistance to emtansine and its metabolites. Instead, we show that hypoxia-induced translocation of caveolin-1 from cytoplasmic vesicles to the plasma membrane contributes to deficient trastuzumab internalization and T-DM1 chemosensitivity. Caveolin-1 depletion mimicked the hypoxic situation, indicating that vesicular caveolin-1 is indispensable for trastuzumab uptake and T-DM1 cytotoxicity. In vitro studies suggested that HER2 and caveolin-1 are not coregulated, which was supported by IHC analysis in patient tumors. We find that phosphorylation-deficient caveolin-1 inhibits trastuzumab internalization and T-DM1 cytotoxicity, suggesting a specific role for caveolin-1 phosphorylation in HER2 trafficking.
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| 5. |
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| 6. |
- Dalmo, Erika, et al.
(författare)
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Growth-Inhibitory Activity of Bone Morphogenetic Protein 4 in Human Glioblastoma Cell Lines Is Heterogeneous and Dependent on Reduced SOX2 Expression
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:7, s. 981-991
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma multiforme continues to have a dismal prognosis. Even though detailed information on the genetic aberrations in cell signaling and cell-cycle checkpoint control is available, no effective targeted treatment has been developed. Despite the advanced molecular defects, glioblastoma cells may have remnants of normal growth-inhibitory pathways, such as the bone morphogenetic protein (BMP) signaling pathway. We have evaluated the growth-inhibitory effect of BMP4 across a broad spectrum of patient samples, using a panel of 40 human glioblastoma initiating cell (GIC) cultures. A wide range of responsiveness was observed. BMP4 sensitivity was positively correlated with a proneural mRNA expression profile, high SOX2 activity, and BMP4-dependent upregulation of genes associated with inhibition of the MAPK pathway, as demonstrated by gene set enrichment analysis. BMP4 response in sensitive cells was mediated by the canonical BMP receptor pathway involving SMAD1/5/9 phosphorylation and SMAD4 expression. SOX2 was consistently downregulated in BMP4-treated cells. Forced expression of SOX2 attenuated the BMP4 sensitivity including a reduced upregulation of MAPK-inhibitory genes, implying a functional relationship between SOX2 downregulation and sensitivity. The results show an extensive heterogeneity in BMP4 responsiveness among GICs and identify a BMP4-sensitive subgroup, in which SOX2 is a mediator of the response.
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| 7. |
- Enokido, Takayoshi, et al.
(författare)
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Distinct microRNA Signature and Suppression of ZFP36L1 Define ASCL1-Positive Lung Adenocarcinoma
- 2024
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Ingår i: Molecular Cancer Research. - : American Association For Cancer Research (AACR). - 1541-7786 .- 1557-3125. ; 22:1, s. 29-40
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Tidskriftsartikel (refereegranskat)abstract
- Achaete-scute family bHLH transcription factor 1 (ASCL1) is a master transcription factor involved in neuroendocrine differentiation. ASCL1 is expressed in approximately 10% of lung adenocarcinomas (LUAD) and exerts tumor-promoting effects. Here, we explored miRNA profiles in ASCL1-positive LUADs and identified several miRNAs closely associated with ASCL1 expression, including miR-375, miR-95–3p/miR-95–5p, miR-124–3p, and members of the miR-17~92 family. Similar to small cell lung cancer, Yes1 associated transcriptional regulator (YAP1), a representative miR-375 target gene, was suppressed in ASCL1-positive LUADs. ASCL1 knockdown followed by miRNA profiling in a cell culture model further revealed that ASCL1 positively regulates miR-124–3p and members of the miR-17~92 family. Integrative transcriptomic analyses identified ZFP36 ring finger protein like 1 (ZFP36L1) as a target gene of miR-124–3p, and IHC studies demonstrated that ASCL1-positive LUADs are associated with low ZFP36L1 protein levels. Cell culture studies showed that ectopic ZFP36L1 expression inhibits cell proliferation, survival, and cell-cycle progression. Moreover, ZFP36L1 negatively regulated several genes including E2F transcription factor 1 (E2F1) and snail family transcriptional repressor 1 (SNAI1). In conclusion, our study revealed that suppression of ZFP36L1 via ASCL1-regulated miR-124–3p could modulate gene expression, providing evidence that ASCL1-mediated regulation of miRNAs shapes molecular features of ASCL1-positive LUADs.
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| 8. |
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| 9. |
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| 10. |
- Johard, Helena, et al.
(författare)
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HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:10, s. 1522-1533
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Tidskriftsartikel (refereegranskat)abstract
- Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are dynamically expressed over the cell cycle in NSCs, depolarize the membrane potential, underlie spontaneous calcium oscillations and are required to maintain NSCs in the actively proliferating pool. Hyperpolarizing pharmacologic inhibition of HCN channels during exposure to ionizing radiation protects NSCs cells in neurogenic brain regions of young mice. In contrast, brain tumor-initiating cells, which also express HCN channels, remain proliferative during HCN inhibition.
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